1-198750486-A-G

Variant names:

• chr1-198750486-A-G
• rs191867796
• NM_002838.5:c.3073-6A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_002838.5(PTPRC):​c.3073-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000365 in 1,611,656 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: PTPRC NM_002838.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002554
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.160
• Publications: 1 publications found

Genes affected

PTPRC (HGNC:9666): (protein tyrosine phosphatase receptor type C) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitosis, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus is classified as a receptor type PTP. This PTP has been shown to be an essential regulator of T- and B-cell antigen receptor signaling. It functions through either direct interaction with components of the antigen receptor complexes, or by activating various Src family kinases required for the antigen receptor signaling. This PTP also suppresses JAK kinases, and thus functions as a regulator of cytokine receptor signaling. Alternatively spliced transcripts variants of this gene, which encode distinct isoforms, have been reported. [provided by RefSeq, Jun 2012]

MIR181A1HG (HGNC:48659): (MIR181A1 host gene)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-198750486-A-G is Benign according to our data. Variant chr1-198750486-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533069.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000513 (78/151938) while in subpopulation AMR AF = 0.00197 (30/15236). AF 95% confidence interval is 0.00142. There are 1 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002838.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRC	NM_002838.5	MANE Select	c.3073-6A>G		splice_region intron	N/A	NP_002829.3
	PTPRC	NM_080921.4		c.2590-6A>G		splice_region intron	N/A	NP_563578.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRC	ENST00000442510.8	TSL:1 MANE Select	c.3073-6A>G		splice_region intron	N/A	ENSP00000411355.3
	PTPRC	ENST00000348564.12	TSL:1	c.2590-6A>G		splice_region intron	N/A	ENSP00000306782.7
	PTPRC	ENST00000697631.1		c.2788-6A>G		splice_region intron	N/A	ENSP00000513363.1

Frequencies

GnomAD3 genomes AF: 0.000514 AC: 78 AN: 151820 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000487 AC: 122 AN: 250692 AF XY: 0.000458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00636

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000327

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000350 AC: 511 AN: 1459718 Hom.: 1 Cov.: 30 AF XY: 0.000368 AC XY: 267 AN XY: 726244

African (AFR) AF: 0.0000599 AC: 2 AN: 33362

American (AMR) AF: 0.000493 AC: 22 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00771 AC: 201 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5746

European-Non Finnish (NFE) AF: 0.000179 AC: 199 AN: 1110416

Other (OTH) AF: 0.00116 AC: 70 AN: 60264

GnomAD4 genome AF: 0.000513 AC: 78 AN: 151938 Hom.: 1 Cov.: 32 AF XY: 0.000539 AC XY: 40 AN XY: 74260

African (AFR) AF: 0.0000723 AC: 3 AN: 41484

American (AMR) AF: 0.00197 AC: 30 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67916

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.000671 Hom.: 0

Bravo AF: 0.000722

EpiCase AF: 0.000437

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Immunodeficiency 104 (2)
-	1	-	Immunodeficiency 105 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.50
PhyloP100		0.16
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs191867796; hg19: chr1-198719615;